Abstract

Individuals who have mutations in the breast-cancer-susceptibility gene BRCA1 (hereafter referred to as BRCA1-mutation carriers) frequently undergo prophylactic mastectomy to minimize their risk of breast cancer. The identification of an effective prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1(mut/+) tissue harbors an aberrant population of luminal progenitor cells1, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis(2-5). Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling(6-10) and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis(11-13), we investigated a role for this pathway in the pre-neoplastic phase of BRCA1-mutation carriers. We identified two subsets of luminal progenitors (RANK(+) and RANK-) in histologically normal tissue of BRCA1-mutation carriers and showed that RANK+ cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. These data suggest that RANK+ and not RANK-progenitors are a key target population in these women. Inhibition of RANKL signaling by treatment with denosumab in three-dimensional breast organoids derived from pre-neoplastic BRCA1mut/+ tissue attenuated progesterone-induced proliferation. Notably, proliferation was markedly reduced in breast biopsies from BRCA1-mutation carriers who were treated with denosumab. Furthermore, inhibition of RANKL in a Brca1-deficient mouse model substantially curtailed mammary tumorigenesis. Taken together, these findings identify a targetable pathway in a putative cell-of-origin population in BRCA1-mutation carriers and implicate RANKL blockade as a promising strategy in the prevention of breast cancer.

Authors	Nolan, Emma; Vaillant, Francois; Branstetter, Daniel; Pal, Bhupinder; Giner, Goeknur; Whitehead, Lachlan; Lok, Sheau W.; Mann, Gregory B.; Rohrbach, Kathy; Huang, Li-Ya; Soriano, Rosalia; Smyth, Gordon K.; Dougall, William C.; Visvader, Jane E.; Lindeman, Geoffrey J.
Journal	NATURE MEDICINE
Pages	933-+
Volume	22
Date	1/08/2016
Grant ID
Funding Body	Victorian Government
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/nm.4118